Method for treating a sleep disorder with a dosage form of besylate salts of zopiclone or eszopiclone

ABSTRACT

Besylate salts of (6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine) are provided.

RELATED APPLICATIONS

This application is a divisional of copending U.S. application Ser. No.12/338,903, which claims priority to U.S. Provisional Application No.61/008,365, filed Dec. 19, 2007. Both applications are incorporated byreference herein in its their entirety.

FIELD OF THE INVENTION

The present invention provides a novel besylate salt of(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine),which exhibits superior taste characteristics and improved aqueoussolubility/dissolution behavior compared to the free base. The besylatesalt is thus useful for pharmaceutical dosage forms, particularly fororal dosage forms.

BACKGROUND OF THE INVENTION

Eszopiclone, also known as (S)-zopiclone or(S)-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine),is formulated as the free base and is sold as LUNESTA®. It is used totreat different types of sleep problems, such as difficulty in fallingasleep, difficulty in maintaining sleep during the night, and waking uptoo early in the morning. Most people with insomnia have more than oneof these problems. See, e.g., WO 93/10787; Brun, J. P., Pharm. Biochem.Behav. 29: 831 832 (1988).

The compound eszopiclone and various methods of treatment are disclosedat least in the following U.S. Pat. Nos. 7,125,874; 6,864,257;6,444,673; 6,319,926; and 5,786,357.

Racemic zopiclone,rac-(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine),also formulated as the free base, has been sold in Europe for many yearsto treat different types of sleep problems.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a composition comprisingthe besylate salt of racemic or enantioenriched zopiclone:(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine),having the formula

as well as pharmaceutical dosage forms thereof.

In another aspect, the present invention provides a compositioncomprising the besylate salt of eszopiclone:(6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine),having the formula

as well as pharmaceutical dosage forms thereof.

It has been found that this besylate salt can exhibit superior tastecharacteristics as well as improved aqueous solubility/dissolutionbehavior compared to the free base.

The invention is also directed towards a method for treating a sleepdisorder in a subject comprising administering to a subject in needthereof the besylate salt of zopiclone or eszopiclone.

In another aspect, the invention provides a method for treating anxietyin a subject comprising administering to a subject in need thereof thebesylate salt of zopiclone or eszopiclone.

In one aspect, the invention provides a composition described abovewherein the composition has at least a one unit difference on anE-tongue analysis relative to eszopiclone.

In another aspect, the invention is directed towards a compositionformed by reacting6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazineand benzenesulfonic acid.

In another aspect, the invention provides a method of making a besylatesalt of6-(5-chloro-2-pyridyl)-5-[4-methyl-1-piperazinyl)carbonyloxy]-7-oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine,comprising the steps of: admixing zopiclone or eszopiclone in one ormore solvents, admixing benzenesulfonic acid with the zopiclone oreszopiclone, and isolating the besylate salt.

In another aspect, the invention provides a method of making a besylatesalt of 6-(5-chloro-2-pyridyl)-5-[4-methyl-1-piperazinyl)carbonyloxy]-7-oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, comprising thesteps of: a) dissolving zopiclone or eszopiclone in an organic solvent;b) heating to form a composition; c) dissolving benzenesulfonic acid ina solvent to form a composition; d) transferring the composition of stepc) to the solution of step b), or transferring the composition of stepb) to the solution of step c), or admixing the composition of step b)and step c); e) cooling to form a salt; and f) isolating the besylatesalt. In certain instances, the composition of step e) is filtered andwashed with one or more solvents. In certain instances, the salt isisolated and in certain instances the salt is dried.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an exemplary dissolution profile of the besylate saltcompared to free base eszopiclone.

DETAILED DESCRIPTION

In one aspect, the present invention provides a composition having theformula

In another aspect, the invention provides a composition having theformula

In another aspect, the invention provides a pharmaceutical dosage formcomprising the besylate salt of zopiclone or eszopiclone and apharmaceutically acceptable carrier.

In another aspect, the invention provides a composition formed byreacting6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazineand benzenesulfonic acid.

As used herein, the terms zopiclone and6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazinerefer to compounds represented by the following structure:

the terms eszopiclone, LUNESTA®, and[(9S)-8-(5-chloropyridin-2-yl)-7-oxo-2,5,8-triazabicyclo[4.3.0]nona-1,3,5-trien-9-yl]-4-methylpiperazine-1-carboxylate refer to an individual enantiomer of theforegoing represented by the following structure:

The besylate salt of the invention contemplates both the racemic mixture(also known as zopiclone), and in certain embodiments, contemplates asingle enantiomer, e.g., the S-enantiomer (eszopiclone). Eszopiclone isthe S-(+)-optical isomer of the compound zopiclone, which is describedin U.S. Pat. Nos. 6,319,926 and 6,444,673, and in Goa and Heel (Drugs,32:48-65 (1986)) and in U.S. Pat. Nos. 3,862,149 and 4,220,646. Thisisomer, which will hereinafter be referred to by its USAN-approvedgeneric name, eszopiclone, includes the optically pure and thesubstantially optically pure (e.g., 90%, 95% or 99% optical purity)S-(+)-zopiclone isomer. As such, the besylate salt of this invention canexist as an individual stereoisomer as well as a mixture ofstereoisomers. Accordingly, the besylate salt of the present inventionwill include not only a stereoisomeric mixture, but also individualrespective stereoisomers substantially free from other stereoisomers. Incertain embodiments, the besylate salt of the invention is directedtowards stereo chemically pure isomers or racemic mixtures. For example,it encompasses non-racemic mixtures of stereoisomers of the samecompound (e.g., about 90, 80, 70, or 60 weight percent of one enantiomerand about 10, 20, 30, or 40 weight percent of the opposite enantiomer);and mixtures of different racemic or stereomerically pure compounds(e.g., about 90, 80, 70, or 60 weight percent of one compound and about10, 20, 30, or 40 weight percent of another).

The compounds of the invention can be synthesized by techniques known inthe art. The starting materials and certain intermediates used in thesynthesis of the compounds of this invention are available fromcommercial sources or can themselves be synthesized using reagents andtechniques known in the art, including those synthesis schemesdelineated herein.

Racemic zopiclone is commercially available and can be made usingvarious methods, such as those disclosed in U.S. Pat. Nos. 3,862,149 and4,220,646.

The synthesis of the besylate salt of the invention can be carried outaccording to the reaction sequence of Scheme 1, and begins withdissolving (S)-zopiclone into an organic solvent. Organic solventsinclude, but are not limited to tetrahydrofuran, diethyl ether,methyl-t-butyl ether, toluene, cumene, chloroform, methylene chloride,hexanes, pentane, heptane, acetone, ethyl acetate, methanol, ethanol,propanol, i-PrOH, and butanol. The contents can be heated to dissolve.The reaction temperature can range from about 25° C. to about 100° C.;in certain embodiments the temperature can range from about 25° C. toabout 50° C.; in certain embodiments the temperature can range fromabout 50° C. to about 100° C.

Benzenesulfonic acid is dissolved into a solvent and is transferredslowly to the zopiclone solution at a temperature ranging from about 25°C. to about 100° C. The reaction is optionally seeded with besylate saltand allowed to cool with stirring and aged. Filtration and washing witha solvent or mixture of solvents is carried out followed by filtration.Mixtures of solvents used for washing and/or filtration include but arenot limited to ratios of 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, and 20:1. Incertain embodiments, mixtures of three organic solvents can be used. Theresulting salt is isolated and dried (optionally under vacuum) at atemperature ranging from about 25° C. to about 100° C., preferably about60° C. to about 65° C., and packaged in an appropriate container.

The compounds of the present invention contain asymmetric carbon atoms.As such, a compound of this invention can exist as an individualstereoisomer as well as a mixture of stereoisomers. Accordingly, acompound of the present invention will include not only a stereoisomericmixture, but also individual respective stereoisomers substantially freefrom other stereoisomers. The term “substantially free” as used hereinmeans less than 25% of other stereoisomers, preferably less than 10% ofother stereoisomers, more preferably less than 5% of other stereoisomersand most preferably less than 2% of other stereoisomers, are present.Methods of obtaining or synthesizing stereoisomers are well known in theart and can be applied as practicable to final compounds or to startingmaterial or intermediates. In another embodiment, the compound is anisolated compound.

Methods for optimizing reaction conditions, if necessary to minimizecompeting by-products, are known in the art. Additional reaction schemesand protocols can be determined by the skilled artesian by use ofcommercially available structure-searchable database software, forinstance, SciFinder® (CAS division of the American Chemical Society) andCrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searchingusing an internet search engine such as Google® or keyword databasessuch as the US Patent and Trademark Office text database.

The synthetic methods described herein can also additionally includesteps, either before or after the steps described specifically herein,to add or remove suitable protecting groups in order to ultimately allowsynthesis of the compound of the formulae described herein.

In certain aspects, the invention provides a method for treating orpreventing various disorders using a zopiclone besylate salt. In oneembodiment, the invention provides a method for treating and/orpreventing sleep disorders, including primary insomnia and sleep-awakerhythm disorders (e.g., work-shift syndrome, time-zone syndrome(jet-lag)).

Insomnia is characterized by difficulty in sleeping or disturbed sleeppatterns. Insomnia can be of a primary nature with little apparentrelationship to immediate somatic or psychic events, or secondary tosome acquired pain, anxiety or depression.

In one aspect, the invention provides a method for treating orpreventing a sleep disorder in a subject comprising administering to asubject in need thereof a salt composition having the formula

such that administration of the salt treats the sleep disorder.

In another aspect, the invention provides a method for treating orpreventing anxiety in a subject comprising administering to a subject inneed thereof a salt composition having the formula

such that administration of the salt treats the anxiety.

As used herein the term “anxiety” refers to an anxiety disorder.Examples of anxiety disorders treatable by the compositions and methodsdisclosed herein include, but are not limited to: panic attack,agoraphobia, acute stress disorder, specific phobia, panic disorder,psychoactive substance anxiety disorder, organic anxiety disorder,obsessive-compulsive anxiety disorder, posttraumatic stress disorder andgeneralized anxiety disorder. Anxiety as referred to herein alsoincludes situational anxiety (e.g. as experienced by a performer priorto a performance).

The named anxiety disorders have been characterized in the DSM-IV-R.Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed.(1994). The DSM-IV-R was prepared by the Task Force on Nomenclature andStatistics of the American Psychiatric Association, and provides cleardescriptions of diagnostic categories.

In a further aspect, the invention provides a use of the besylate saltof zopiclone, particularly eszopiclone, for the treatment or preventionof a disorder disclosed herein. In a preferred embodiment, the disorderis sleep disorders or anxiety.

In a yet further aspect, the invention provides a use of the besylatesalt of zopiclone, particularly eszopiclone, for the preparation ofmedicament for the treatment or prevention of a disorder disclosedherein. In a preferred embodiment, the disorder is sleep disorders oranxiety.

Preferred methods and uses of the invention include identifying and/orselecting a subject, particularly a human subject, that is susceptibleto or suffering from a disorder disclosed herein, and thereafteradministering to the identified and selected subject the besylate saltof zopiclone, particularly eszopiclone. In certain embodiments, thedisorder is sleep disorders or anxiety. Such identification andselection can be made e.g., by a physician or other health professional.

Other disorders treated by the invention include seasonal melancholia,genital disorder, neuroendocrine disorder, senile dementia, Alzheimer'sdisease, various disorders accompanied by aging, cerebrovasculardisorders (e.g. cerebral hemorrhage, etc.), cranial injury, spinalinjury, epilepsy, depression, manic-depressive psychosis, schizophrenia,alcoholism, Parkinson's disease, hypertension, arteriosclerosis,arrhythmia, premenstrual tension syndrome, glaucoma, metabolic disorders(e.g., obesity, insulin resistance, etc.), cancer, AIDS and diabetes inmammals (e.g. human, cat, dog, monkey, etc.). In addition, it is alsoeffective for protection against aging, immunoregulation, and ovulatoryregulation (e.g., contraception).

In one embodiment, the invention provides a method of treating orpreventing a disease or condition which is affected by the modulation ofone or more central benzodiazepine sites in a subject which comprisesadministering to a subject in need of such treatment or prevention atherapeutically or prophylactically effective amount of a zopiclonebesylate salt. Such disorder include but are not limited to anxiety;affective disorders such as depression, attention deficit disorder(“ADD”), and attention deficit disorder with hyperactivity (“ADDH”) orattention deficit/hyperactivity disorder (“ADHD”); convulsive disorderssuch as epilepsy; aggressive behavior; spasticity or acute muscle spasm;behavioral disorders such as mood anxiety and schizophrenia; and alcoholand drug addiction.

Another embodiment of the invention encompasses a method of treating orpreventing anxiety in a subject which comprises administering to asubject in need of such treatment or prevention a therapeutically orprophylactically effective amount of a zopiclone besylate salt. Theanxiety can be acute or chronic anxiety, or can be a general anxietydisorder. In certain embodiments, the invention provides for reducingthe severity of at least one symptom associated with acute anxiety,chronic anxiety, general anxiety disorder caused by psychologic and/orphysiologic factors, and other anxiety disorders such as panicdisorders, mood anxiety, panic attacks, phobias, obsessive-compulsivedisorders, or post traumatic distress disorder. Symptoms associated withacute anxiety include, but are not limited to, a fear of losing controlof one's own actions, a sense of terror arising from no apparent reason,and a dread of catastrophe. Symptoms associated with chronic anxietyinclude, but are not limited to, uneasiness, nervousness, nagginguncertainty about future events, headache, fatigue, and subacuteautonomic symptoms.

Another embodiment of the invention encompasses a method of treating orpreventing a convulsive state in a subject which comprises administeringto a subject in need of such treatment or prevention a therapeuticallyor prophylactically effective amount of a zopiclone besylate salt. Aparticular method of this embodiment is the treatment or prevention ofepilepsy or epileptic seizures. In a further embodiment, the inventionprovides for reducing the severity and/or frequency of at least onesymptom associated with convulsive states which include, but are notlimited to, recurrent, sudden, and often brief alterations ofconsciousness, motor activity, sensory phenomena, and autonomicresponses which are often characterized by convulsive seizures and/ortonic or clonic jerking of the extremities. The term “convulsive state”encompasses epilepsy and specific types of epileptic seizures including,but not limited to, Tonic-clonic (Grand Mal), Partial (Focal) seizures,psychomotor (Complex partial) seizures, pyknoepileptic or Absence (PetitMal) seizure, and Myoclonic seizures.

Another embodiment of the invention encompasses a method of treating orpreventing an affective disorder in a subject which comprisesadministering to a subject in need of such treatment or prevention atherapeutically or prophylactically effective amount of a zopiclonebesylate salt. A particular method encompassed by this embodiment is thetreatment or prevention of depression. Another method encompassed bythis embodiment is the treatment or prevention of attention deficitdisorder or attention deficit disorder with hyperactivity. The phrase“treating or preventing an affective disorder” means reducing theseverity of at least one symptom associated with a psychologicaldisorder characterized by abnormality of emotional state, including butnot limited to, depression, dysthymia, attention deficit disorder,attention deficit disorder with hyperactivity, bipolar disorders,bipolar and manic conditions, and the like. The terms “attention deficitdisorder” (“ADD”) and “attention deficit disorder with hyperactivity”(“ADDH”), or “attention deficit/hyperactivity disorder” (“ADHD”), areused herein in accordance with the accepted meanings as found in theDiagnostic and Statistical Manual of Mental Disorders, 4th Ed., AmericanPsychiatric Association (1997). In one embodiment, the phrase “treatingor preventing depression” means reducing the severity of at least onesymptom associated with depression which include, but are not limitedto, changes in mood, feelings of intense sadness, despair, mentalslowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Symptoms associated with depression can also bephysical symptoms, which include, but are not limited to, insomnia,anorexia, weight loss, decreased energy and libido, weight gain, andabnormal hormonal circadian rhythms.

Another embodiment of the invention encompasses a method of treating orpreventing aggressive behavior in a subject, which comprisesadministering to a subject in need of such treatment or prevention atherapeutically or prophylactically effective amount of a zopiclonebesylate salt. In certain embodiments, the method includes reducing thefrequency and/or severity of at least one manifestation of aggressivebehavior which include, but are not limited to, aggressive or sociallyinappropriate vocal outbursts and acts of physical violence.

Another embodiment of the invention encompasses a method of treating orpreventing spasticity or acute muscle spasm spasticity in a subjectwhich comprises administering to a subject in need of such treatment orprevention a therapeutically or prophylactically effective amount of azopiclone besylate salt. In certain instances the invention provides amethod of “treating or preventing spasticity,” “treatment and preventionof spasticity,” “treating or preventing spasticity and acute musclespasm,” and “treatment and prevention of spasticity and acute musclespasm,” which includes reducing the severity of at least one symptomassociated with a range of abnormalities of skeletal muscle regulationthat result from problems of the nervous system. A predominant symptomis heightened muscle tone or hyper-excitability of tonic stretch musclereflexes. Symptoms of acute muscle spasm include, but are not limitedto, trauma, inflammation, anxiety, and pain.

Another embodiment of the invention encompasses a method of treating orpreventing a behavioral disorder in a subject which comprisesadministering to a subject in need of such treatment or prevention atherapeutically or prophylactically effective amount of a zopiclonebesylate salt. The phrase “treating or preventing a behavioral disorder”means reducing or relieving from at least one symptom of a behavioraldisorder, which include, but are not limited to, a subjective sense ofterror, a dread of catastrophe, uneasiness, nervousness, uncertainty,headache, fatigue, disturbed thinking, inappropriate effect, auditoryhallucinations, and aggressive outbursts.

Another embodiment of the invention encompasses a method of treating orpreventing a schizophrenic disorder in a subject which comprisesadministering to a subject in need of such treatment or prevention atherapeutically or prophylactically effective amount of a zopiclonebesylate salt. The phrase “treating or preventing a schizophrenicdisorder” means reducing the severity of at least one symptom associatedwith schizophrenic disorders. Symptoms of schizophrenic disordersinclude, but are not limited to, psychotic symptoms of disturbedthinking, feeling and general behavior. Specific symptoms ofschizophrenic disorders include the inability to form clear,goal-directed thought, and emotional changes such as blunting andinappropriate affect. Other symptoms of schizophrenic disorders includeauditory hallucinations, delusions of persecution, threats of violence,minor aggressive outbursts, aggressive behavior, disturbances ofmovement such as significant overactivity and excitement, andretardation and stupor.

Another embodiment of the invention encompasses a method of treatingalcohol or drug addiction in a subject which comprises administering toa subject in need of such treatment a therapeutically orprophylactically effective amount of a zopiclone besylate salt. As usedherein, the phrase “treating alcohol or drug addiction” means reducingat least one symptom of disease or conditions related to alcohol or drugaddiction including, but not limited to, drug or alcohol addiction orsymptoms of withdrawal from alcohol or drugs. Symptoms of withdrawalinclude, but are not limited to, depression, pain, fever, restlessness,lacrimation, rhinorrhea, uncontrollable yawning, perspiration,piloerection, restless sleep, mydriasis, twitching and muscle spasms,severe aches in the back, abdomen and legs, abdominal and muscle cramps,hot and cold flashes, insomnia, nausea, vomiting, diarrhea, coryza andsevere sneezing, and increases in body temperature, blood pressure,respiratory rate, and heart rate. Another embodiment of the inventionencompasses a method of treating or preventing drug withdrawal, alcoholwithdrawal, symptoms of drug withdrawal, or symptoms of alcoholwithdrawal in a subject which comprises administering to a subject inneed of such treatment a therapeutically or prophylactically effectiveamount of a zopiclone besylate salt.

In another aspect, the invention provides a use of the besylate salt ofthe invention in the manufacture of a medicament for treating orpreventing any one of the disorders disclosed herein in a patient.

In one embodiment, the invention provides a use of the besylate salt ofthe invention in the manufacture of a medicament for treating orpreventing sleep disorder in a patient.

In one embodiment, the invention provides a use of the besylate salt ofthe invention in the manufacture of a medicament for treating orpreventing anxiety in a patient.

In certain aspects, the racemic zopiclone can be utilized herein in thesame manner as described for the S-isomer eszopiclone. However, it isrecognized that use of eszopiclone can provide advantages over use ofthe racemic zopiclone and thereafter use of eszopiclone will bepreferred for many applications.

In a specific method, the zopiclone besylate salt used in the treatmentof the above disorders is stereomerically pure.

The term “treating” or “treated” refers to administering a compounddescribed herein to a subject with the purpose to cure, heal, alleviate,relieve, alter, remedy, ameliorate, improve, or affect a disease, thesymptoms of the disease or the predisposition toward the disease.

“An effective amount” refers to an amount of a compound, which confers atherapeutic effect on the treated subject. The therapeutic effect can beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect). Effective doses willalso vary depending on route of administration.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing,” “prevention,” and “prophylactic” refer to the preventionof the onset, recurrence or intensification of a disorder disclosedherein. The terms “prevent,” “preventing,” “prevention,” and“prophylactic” include ameliorating and/or reducing the occurrence ofsymptoms of a disorder disclosed herein.

Physical Properties of Salt

The besylate salt described above has exhibited improved tastecharacteristics relative to the free base compound, as demonstrated inthe examples which follow. Taste assessments were made with“Electronic-tongue” (E-tongue) analysis systems and also in human tastetrials. Preferred salt compounds have at least a one unit difference onan E-tongue analysis relative to eszopiclone, more preferably at least a2 or 3 unit difference on an E-tongue analysis relative to eszopiclone.E-tongue analysis is suitably performed as described in Example 4 whichfollows using E-tongue apparatus commercially available from Alpha-mos(Hillsborough, N.J.). As referred to herein, a specified unit differenceon an E-tongue analysis refers to a value using a protocol as specifiedin Example 3 which follows.

The results in the E-tongue analysis are bolstered by the finding thatthe besylate salt exhibits less bitterness than the free base whentested with human subjects as described in Example 6 below.

It also has been found that the present salt compounds exhibit goodsolubility and dissolution characteristics, as shown in Example 5 whichfollows.

The present invention relates to pharmaceutical compositions containingthe besylate salt of the dextrorotatory isomer of zopiclone, thelevorotatory isomer of zopiclone, or its racemic mixture, in the purestate or in the presence of a diluent or a coating. These compositionscan be employed orally, rectally or parenterally.

Pharmaceutical compositions and dosage forms of the invention compriseone or more of the active ingredients disclosed herein. Pharmaceuticalcompositions and dosage forms of the invention typically also compriseone or more pharmaceutically acceptable excipients or diluents.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and iscommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound or a prodrug of a compound of this invention. A“pharmaceutically acceptable counterion” is an ionic portion of a saltthat is not toxic when released from the salt upon administration to arecipient.

The invention also provides compositions comprising an effective amountof the besylate salt of zopiclone and an acceptable carrier. Preferably,a composition of this invention is formulated for pharmaceutical use (“apharmaceutical composition”), wherein the carrier is a pharmaceuticallyacceptable carrier. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and, inthe case of a pharmaceutically acceptable carrier, not deleterious tothe recipient thereof in amounts typically used in medicaments.

Pharmaceutically acceptable carriers, adjuvants and vehicles that can beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Preparative methods include the step of bringing into association withthe molecule to be administered ingredients such as the carrier thatconstitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers or both, and then if necessary shaping theproduct.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disorder can contain larger amounts of oneor more of the active ingredients it comprises than a dosage form usedin the chronic treatment of the same disease. Similarly, a parenteraldosage form can contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease or disorder. These and other ways in which specific dosage formsencompassed by this invention will vary from one another will be readilyapparent to those skilled in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets can contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient can also depend on the specific active ingredientsin the dosage form. For example, the decomposition of some activeingredients can be accelerated by some excipients such as lactose, orwhen exposed to water. This invention encompasses pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art. In general, lactose-free compositionscomprise active ingredients, a binder/filler, and a lubricant inpharmaceutically compatible and pharmaceutically acceptable amounts.Preferred lactose-free dosage forms comprise active ingredients,microcrystalline cellulose, pre-gelatinized starch, and magnesiumstearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379 80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and can be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentscan be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

The besylate salt of zopiclone can, for example, be administered with adosage ranging from about 0.001 to about 0.2 mg/kg of body weight,alternatively dosages between 0.1 mg and 15 mg/dose, or between about0.1 mg and about 10 mg/dose, or preferably between about 0.2 mg andabout 5 mg/dose, or according to the requirements of the particulartherapy. The methods herein contemplate administration of an effectiveamount of compound or compound composition to achieve the desired orstated effect. Typically, the pharmaceutical compositions of thisinvention will be administered from about 1 to about 6 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that canbe combined with the carrier materials to produce a single dosage formwill vary depending upon the host treated and the particular mode ofadministration. In some embodiments, such preparations contain fromabout 20% to about 80% (w/w) active compound. In some embodiments, suchpreparations contain from about 0.5% to about 20% active compound. Atypical preparation will contain from about 0.5% to about 5% activecompound (w/w).

Lower or higher doses than those recited above can be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form can differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In human therapy, the doses depend on the effect sought andthe treatment period; taken orally, they are generally between 0.5 and15 mg per day for an adult. For many applications, unit dosagescontaining 0.5 mg, 1 mg, 2 mg or 3 mg of a present eszopiclone salt willbe suitable. In some embodiments, the unit dosages of the eszopiclonesalts can be adjusted to contain the molar equivalent of 0.5 mg, 1 mg, 2mg or 3 mg of eszopiclone freebase.

The following non-limiting examples are illustrative of the invention.

EXAMPLE 1 Synthesis of (S)-Zopiclone Besylate

A 2000 mL reactor was charged with 10.0 g (S)-zopiclone and 400 mLtetrahydrofuran (THF). The contents were heated to 35° C. Into a 1000 mLreactor was charged 4.4 g benzenesulfonic acid and 400 mL THF, andstirred until a solution was formed. The acid solution was transferredslowly to the zopiclone solution. The reaction was cooled to 15° C. andstirred for 18 hr at 20-25° C. The reactor slurry was filtered andwashed with THF in an appropriate filter. The wet cake was dried undervacuum at 60-65° C. and packaged in an appropriate container. Isolatedyield=92.7%.

EXAMPLE 2 Synthesis of (S)-Zopiclone Besylate

A reactor was charged with 0.123 g (S)-zopiclone. To the reactor wasadded 0.056 g benzenesulfonic acid. The reaction was agitated andcharged with 17.2 g ethanol. The reaction was cooled to 0° C., and thereaction was allowed to stir for greater than one hour after a slurryappeared. The reaction mixture was filtered and washed once with 0.5 gethanol, dried in vacuo at approximately 50° C. for approximately 6 h toyield the titled compound in 52% yield.

EXAMPLE 3 Synthesis of (S)-Zopiclone Besylate

Eszopiclone free base (10.0 g) was dissolved in tetrahydrofuran (THF)solvent (441.0 g) by mixing and heating between 45-55° C. in a reactorvessel. Benzenesulfonic acid (4.27 g) was dissolved in THF (348.0 g) anda small portion (˜10%) was added to the eszopiclone free base solution.Eszopiclone besylate seed (˜250 mg) was added to the solution. Themixture was aged for 30 minutes. The remainder of the besylate solutionwas added slowly to the reactor. The product slurry was then heated to63-67° C. and was allowed to age for a minimum of 30 minutes. Theproduct slurry was slowly cooled to 15° C. and mixed for a minimum of 20minutes. The reaction was filtered and washed once with 100 gtetrahydrofuran, dried in vacuo until no further weight loss at 55° C.(˜6 h) to provide the titled compound in 97% yield.

EXAMPLE 4 Bitterness Results using E-Tongue

The α Astree II Bitterness Prediction Module (BPM) and Electronic Tongue(E-Tongue) was utilized to perform taste assessments. The sensory(E-tongue) apparatus utilized is commercially available (Alpha-mos,Hillsborough, N.J.) and includes three arrays of seven sensors with thethird array utilized to assess bitterness of chemical identities. Thebitterness results were obtained with the α Astree II BPM used in apharmaceutical configuration for bitterness assessment of eszopiclone,and its besylate salt form prepared at various concentrations using thethird sensor array.

When analyzing a sample on the α Astree II Electronic Tongue, basicparameters/experimental conditions, such as analysis time and stirringrate per sample were established in accordance with standard operationof the analysis system. The various methods were saved on the BPM forthe analysis of each test sample. Each method utilized all seven sensors(BD, EB, JA, JG, KA, OA, and OB) on sensor array 3 to perform aninstrumental characterization of the prepared formulations.

Solutions of caffeine (0.05 and 0.5 mg/mL), acetaminophen (0.5 and 3.0mg/mL), quinine (0.04 and 0.01 mg/mL), and prednisolone (0.25 and 0.5mg/mL), were prepared to create a calibration curve, partial leastsquare (PLS) to correlate the sensory panel scores and themeasurements/values obtained from the prepared solutions of eszopicloneand its besylate salt forms from the BPM.

Eszopiclone and its besylate salt were prepared as solution in deionizedwater at freebase equivalent concentrations of 0.002 mg/mL and 0.02mg/mL for analysis.

BPM data analysis model is based on a Partial Least Square PLSstatistical data treatment. The PLS model allowed for correlation of theinstrument result (sensor responses) to a BU (Bitterness Unit) definedby the sensory panel. The proposed scale of BU is from 1 to 20, whichrespectively corresponds to a non detectable bitterness and anunacceptable bitterness.

The in vivo measurements were then performed on a 1-20 scale where thebitterness intensity increases for higher marks. This scale was dividedinto 5 different categories: non detectable bitterness from marks 1 to4.5; slight bitter taste from marks 4.5 to 8.5; acceptable bitternessfrom marks 8.5 to 12.5; limit but acceptable bitterness from marks 12.5to 16.5; and non acceptable bitterness from marks 16.5 to 20. Theresults of the e-tongue data are provided in Table 1. Table 1 shows thatthe besylate salt has a predicted bitterness of 10.4 at 0.02 mg/mL, anda predicted bitterness of 8.7 at 0.002 mg/mL. Desirable compositionshave at least a one unit difference on an E-tongue analysis relative tocontrol (in this case the corresponding free base).

TABLE 1 Average Predicted Bitterness Average Predicted SampleConcentration Bitterness Free base  0.02 mg/ml 15.6 0.002 mg/ml 8.4Besylate  0.02 mg/ml 10.4 0.002 mg/ml 8.7

EXAMPLE 5 Solubility and Dissolution

The aqueous solubility was determined by taking a filtered aliquot of anequilibrated (24 hour at ambient) suspension of the salt in water. Thealiquot was diluted and analyzed by HPLC (Waters). The data was comparedto a standard curve generated from a set of solutions of knownconcentrations. The standard curve and the samples were analyzed using aHPLC using the following conditions:

-   -   Column: Symmetry C-18, 5 um, 15 cm×3.9 mm (Waters)    -   Mobile Phase: 0.05 M KH₂PO₄—0.01M Hexanesulfonic Acid/THF        (1000:125) (Apparent pH 5.0)    -   Column Temp: 20-30° C.    -   Flow Rate: 1.0 mL/min    -   Wavelength: 305 nm    -   Run Time: 15 min (zopiclone retention time is 9.5-10 min)

TABLE 2 Water Solubility Data for Eszopiclone Salts Solubility Compound(mgA/mL) pH² Freebase 0.2¹ 7.6 Besylate 34 4.4 ¹24-hour value;experiment stopped because significant degradation was observed ²pHmeasured at saturation.

The intrinsic dissolution (Table 3) was determined using USP 28 method<1087> (United States Pharmacopeia, The National Formulary, USP 28,28^(th) edition, Rockville, Mass., 2005). Preparation of each testsample was performed as per USP 28 method <1087> by weighing andtransferring the material to the die cavity and compressing for 1 minuteat the minimum compression pressure necessary to form anondisintegrating compacted pellet. The dissolution media used wasisotonic 50 mM acetate buffer (pH 4.5) at 37° C. and speed was set at 50rpm. Each run was halted at 5 min, irrespective of the percentdissolved. Each salt was run in duplicate.

TABLE 3 Intrinsic Dissolution Data for Eszopiclone Salts in Isotonic 50mM Acetate (pH 4.5) Buffer at 37° C. Run 1 Run 2 Average Compound(mgA/cm²/min) (mgA/cm²/min) (mgA/cm²/min) Freebase 0.6 0.5 0.5 Besylate3.3 2.6 2.9

Dissolution over time of eszopiclone besylate salt was compared to thatof free base at room temperature (FIG. 1) in pH 4.5 20 mM acetate bufferusing Hanson Research SR8-Plus Dissolution Apparatus and C-TechnologiesFiber Optic Probes. A standard dissolution protocol was used. Forexample, 100.12 mg eszopiclone free base (MW 388.81) or 140.93 mgeszopiclone besylate salt (MW 546.99; purity 99.8%) was added to anempty vessel. 500 ml of pH 4.5 20 mM acetate buffer was added to each ofthe vessels and mixed at 50 rpm paddle speed. The dissolution programwas started immediately and readings were taken at 350 nm for 60 min(every 1 min for 10 min and then every 10 min). Each sample was run intriplicate.

EXAMPLE 6 Bitterness Results in an Open-Label Taste Assessment inHealthy Human Subjects

The Flavor Profile is an art-recognized descriptive sensory analysismethod used to measure the type and intensity of attributes in productsand ingredients. [see Keane, P. The Flavor Profile Method. In C. Hootman(Ed.), Manual on Descriptive Analysis Testing for Sensory EvaluationASTM Manual Series: MNL 13. Baltimore, Md. (1992).] It is based on theconcept that flavor consists of identifiable taste, odor (aroma), andchemical feeling attributes, plus an underlying complex of attributesnot separately identifiable. The method consists of formal proceduresfor describing and assessing the flavor of a product in a reproduciblemanner.

Seven-point scales are used to measure the intensity or strength of theflavor character notes as well as the amplitude, as shown below:

Value Intensity Amplitude 0 None None ½ Very Slight Very Low 1 SlightLow 1½ Slight-to-Moderate Low-to-Moderate 2 Moderate Moderate 2½Moderate-to- Moderate-to- Strong Strong 3 Strong Strong

Intensity is a constant scale; that is, when sweetness is designated ata slight-to-moderate strength (1½) in both chocolate and orange juice,for example, the sweetness level detected can be related to referencematerials of a slight-to-moderate level of sweetness exemplified by acertain concentration of sugar (sucrose). A description of aftertaste,the sensations that are still present in the mouth after swallowing, isalso included in the Flavor Profile. Aftertaste was measured in terms ofintensity ratings at various time intervals.

For the purpose of testing the compounds of the invention, the flavorprofile panel consisted of four persons who have normal ability to smelland taste, have been trained in fundamental sensory principles and allaspects of the Flavor Profile technique and have considerable experienceas panel members. The samples to be profiled were uniform andrepresentative. Sample preparation and presentation were standardizedand controlled. Each panel member received an aliquot for his/her ownindependent analysis.

Eszopiclone besylate was evaluated as a solution in water. Each panelistconstituted his/her individual sample and mixed the solution with amagnetic stirrer for 20 minutes. The samples were prepared at 0.01 mg/5mL, 1.0 mg/5 mL and 3.0 mg/5 mL. The 0.01 mg/5 mL concentration isbelieved to approximate a concentration that could be encountered duringthe brief period that a 3 mg tablet resides in the typical patient'smouth. For that reason, the results at 0.01 mg/5 mL are considered mostclinically relevant. The 1.0 mg/5 mL concentration is probably the upperlimit for exposure and would be considered quite uncommon. Achieving a3.0 mg/5 mL concentration under normal conditions of oral administrationwould require chewing the whole tablet, which is considered not relevantfor the present purposes. The panelists sipped the full 5 mL solution,swished it around the oral cavity and expectorated after 10 seconds.During this time the panelists independently evaluated and recorded theinitial flavor characteristics. The panelists then independentlyevaluated and recorded the aftertaste characteristics at 1, 3, 5, 10,15, 20, 25 and 30 minutes. The taste element that is most noticed bypatients taking eszopiclone free base is bitterness. The results of thetest for bitterness are shown in the following table:

TABLE 4 Human Taste Bitterness Results for Eszopiclone Besylate Saltdose t = 0 t = 1 t = 3 t = 5 t = 10 t = 15 t = 20 t = 25 t = 30 0.01mg/5 mL 1.6 1.7 1.7 1.5 1.3 1.1 0.9 0.6 0.4 free base 0.01 mg/5 mL 1.01.3 1.4 1.2 0.9 0.7 0.6 0.3 0.2 salt 1.0 mg/5 mL 2.7 2.8 2.6 2.4 2.2 2.01.8 1.5 1.4 free base 1.0 mg/5 mL 2.7 3.0 2.8 2.4 2.3 2.1 1.8 1.8 1.7salt

Although the salt was tested at 3.0 mg/5 mL, the free base was not, socomparative data are not available.

EXAMPLE 7 Exemplary Compositions

Suitable ingredients of a tablet dosage form using eszopiclone besylateas the active ingredient are provided in Table 5. Tablets containing 3mg of active product and having the following composition can beprepared according to a usual technique:

TABLE 5 Exemplary Composition Besylate Salt 0.003 g* MicrocrystallineCellulose 0.060 g Calcium Phosphate 0.035 g Magnesium Stearate 0.005 g*Adjust to contain molar equivalent of 0.003 g of freebase eszopiclone

Tablets of other strengths can be prepared by altering the ratio ofactive ingredient to pharmaceutically acceptable carrier, thecompression weight, or by using different punches.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, technical datasheets, internet web sites, databases, patents, patent applications, andpatent publications. In case of conflict, the present application,including any definitions herein, will control.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A method for treating a sleep disorder in a subjectcomprising administering to a subject in need thereof a pharmaceuticaldosage form comprising a besylate salt of zopiclone and apharmaceutically acceptable carrier, such that administration of thedosage form treats the sleep disorder.
 2. A method for treating a sleepdisorder in a subject comprising administering to a subject in needthereof a pharmaceutical dosage form comprising a besylate salt ofeszopiclone and a pharmaceutically acceptable carrier, such thatadministration of the dosage form treats the sleep disorder.